The intravenous injection of F1 hybrid mice with parental spleen cells resulted in a loss in the ability of the F1 mice to generate T-cell mediated cytotoxic responses in vitro to TNP-self and alloantigens. The loss of response potential depended on the H-2 type of the parental cells, since H-2k,a spleen cells induced unresponsiveness, whereas H-2b spleen cells did not. The phenomenon is dependent on recognition of F1 I-A alloantigens by grafted parental cells (GVH), since loss of immune activity was associated with enlarged F1 host spleens. Suppressor cells were found to be responsible for loss of immune potential. The failure of lymphocytes from parental strains was shown to be due to F1 resistance to parental T cells, which mapped to H-2Db. Protection against GVH-associated suppression could be achieved using anti-H-2 sera directed against specificities of donor or host. This antisera activated a counter-suppressor T cell which could be demonstrated in either host or donor spleen cell populations. Allogeneic combinations of donor and recipient strains also resulted in suppression. Suppression was observed in combinations of donors and hosts in which host-vs-graft reactions occurred. Chimerism was observed in some but not all parent-into-F1 combinations.